Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

Br J Cancer. 1988 Apr;57(4):395-402. doi: 10.1038/bjc.1988.89.

Abstract

We investigated 5-azacytidine and five of its analogues for: (1) carcinogenicity, in the male Fischer rat; (2) toxicities using changes in rat weights in vivo and a cytotoxicity assay in vitro; and (3) haemoglobin gene expression, using minor haemoglobin synthesis in sheep, mice and rats. 5-Azacytidine was found to be a complete carcinogen. It increased the incidence of testicular tumours as well as non-testicular tumours in rats treated for 12 months. 5-Azacytidine also had hepatic tumour promoting properties and was able to induce transplacental carcinogenesis when administered to pregnant rats on day 21 of timed pregnancies. None of the other 5 analogues that were tested appeared to be carcinogenic in small experiments. All the analogues which are known to have hypomethylating activity were found to be cytotoxic in vitro; the most potent being 5-azacytidine. As judged by decreased rat weight compared to untreated controls, the fluorinated cytidine analogues and 5'-deoxyazacytidine were more toxic than 5-azacytidine. Altered haemoglobin synthesis was seen in rats and DBA/2J mice, but not in sheep. In mice, where the clearest haemoglobin changes were noted, an increase in minor haemoglobin synthesis was found using both high and low doses of 5-azacytidine, and with 5,6-dihydro-5-azacytidine and 5-aza-2'-deoxycytidine. These last two analogues appear to be relatively non-toxic, noncarcinogenic in these experiments, and retain haemoglobin activating properties with a potency similar to that of 5-azacytidine.

MeSH terms

  • Animals
  • Azacitidine / analogs & derivatives
  • Azacitidine / toxicity*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Hemoglobins / biosynthesis*
  • Leydig Cell Tumor / chemically induced
  • Liver Neoplasms, Experimental / chemically induced
  • Male
  • Mice
  • Mice, Inbred DBA
  • Neoplasms, Experimental / chemically induced*
  • Rats
  • Rats, Inbred F344
  • Sheep
  • Testicular Neoplasms / chemically induced

Substances

  • Hemoglobins
  • Azacitidine